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June 9 — AstraZeneca Pharmaceuticals wants the FDA to wait until 2023 to approve generics
of its cholesterol treatment Crestor, citing an exclusivity period for a rare-disease
use.

Crestor is set to lose market exclusivity July 8 when a six-month period of pediatric
exclusivity on Crestor's main compound patent expires.

That means that the Food and Drug Administration could approve additional generics
of Crestor as soon as next month, a development that AstraZeneca would like to keep
from happening.

The drugmaker filed a
citizen petition, released June 6, to try to prevent the FDA from approving generic Crestor copies
until 2023. The 2023 date Astra refers to is the expiration of the branded drugmaker's
orphan or rare-disease drug exclusivity for one specific indication.

Currently, there are several abbreviated new drug applications (ANDAs) for generic
Crestor awaiting approval at the FDA.

With the possibility of agency approval of those generic applications looming in July,
AstraZeneca is also asking the FDA to expedite its review of its petition.

AstraZeneca's petition says that the agency doesn't have the authority to approve
generic applications for Crestor (rosuvastatin calcium) until 2023, because of the
orphan drug exclusivity.

Huge Revenue Losses Expected

Crestor has been a blockbuster product for AstraZeneca. Global sales of Crestor totaled
$5 billion in 2015, Bloomberg Gadfly health-care columnist Max Nisen said June 10.

For AstraZeneca, the financial repercussions of multiple generic versions of Crestor
entering the market are likely to be “big and quick,” he told Bloomberg BNA.

In 2016, Nisen said, the consensus is that Crestor global sales will drop to $3.5
billion, a 30 percent drop-off in revenue.

“AstraZeneca's petition makes sense,” Nisen said, both because of the huge drop-off
in revenue that's expected to occur once multiple Crestor generics start hitting the
market and because of the FDA's continuing efforts to reduce the backlog of generic
drug applications at the agency.

In February, AstraZeneca warned investors that profit and sales would decline in 2016
because both Crestor and Nexium, which treats heartburn, were set to lose patent protection
in the U.S. (14 PLIR 212, 2/12/16).

The drugmaker's petition to the FDA is an attempt to stanch some of that bleeding,
Nisen said.

AstraZeneca Petitions FDA

In the petition, the drugmaker says that the FDA doesn't have the authority to approve
generic applications for Crestor (rosuvastatin calcium) until 2023 because the product
has orphan drug exclusivity.

Under the Orphan Drug Act of 1983, the FDA can award seven years of marketing exclusivity
to reward companies for developing drugs to treat rare conditions and diseases. Rare
or “orphan” diseases are defined as those that affect 200,000 or fewer Americans.

Crestor is protected from new generic competition until May 27, 2023, by orphan drug
exclusivity for an indication covering children with homozygous familial hypercholesterolemia
(“HoFH”), a rare disorder involving extremely high cholesterol, the petition says.

`Carve-Out' Generics Unsafe?

Although the FDA can approve generics as “carve-out” generics, meaning not all of
the uses listed on the branded drug's label appear on the generic label, AstraZeneca
says that's not appropriate for Crestor.

Allowing the FDA to approve generic versions of Crestor as carve-outs would create
substantial safety and efficacy risks, AstraZeneca told the agency.

“Although FDA may in some instances approve ANDAs that omit protected pediatric labeling,
FDA has made clear that a carve out is inappropriate when, as here, the protected
pediatric labeling is ‘necessary for the safe use of the drug.' ,” the petition said.

Court Decision Was Incorrect?

AstraZeneca also argued that a federal trial court's decision holding that the FDA
had the authority to carve out pediatric labeling protected by orphan drug exclusivity
for the schizophrenia drug Abilify was “incorrect and should be overturned” (13 PLIR 802, 6/5/15).

The petition, dated May 31, doesn't address a subsequent decision from a three-judge
panel of the U.S. Court of Appeals for the D.C. Circuit that upheld the FDA's approval
of Sandoz's “carved-out” generic version of Spectrum Pharmaceuticals Inc.'s injectable
cancer drug Fusilev (14 PLIR 835, 6/10/16). The panel said that the agency's decision to approve the generic drug and allow
the generic drug manufacturer to omit an indication protected by orphan drug exclusivity
didn't violate Spectrum’s exclusivity rights.

Will Petition Succeed?

Terry G. Mahn, an attorney with Fish & Richardson P.C. in Washington, who is an expert
in patent and exclusivity matters, said he's not convinced that AstraZeneca's latest
gambit will work.

“This is a complicated issue,” he told Bloomberg BNA June 10. “Put simply, it is about
the law of pediatric labeling for generic drugs when exclusivity rights are involved;
and more specifically, it is about when those rights are orphan drug exclusivity.”

“Astra thinks it has found a way to use orphan exclusivity for a pediatric indication
(for Crestor) to block generics that would otherwise be approvable for nonpediatric
indications,” he said. “I am skeptical.”

“Why am I skeptical?
Because FDA has found clever ways in the past of getting around the ‘same labeling'
rule for three-year exclusivity and patents … by allowing the generic to ‘monkey'
with label information,”
he said.

Mahn said the FDA “could find a clever way to get around the ‘no less safe or effective'
rule if it puts its mind to it.”

“Astra is banking on FDA not being able to do this,” Mahn said. “I am not so sure.”

AstraZeneca's Financial Strategy

In the meantime, AstraZeneca has been aggressive in trying to come up with alternative
sources of revenue to replace the losses from its blockbusters, Nisen said, with a
particular focus on beefing up the oncology area.

“They have a promising set of drugs in the pipeline,” he said, noting that the company
recently has been on a buying spree, actively acquiring other drug companies.

In November 2015, AstraZeneca agreed to buy ZS Pharma for $2.7 billion in cash, acquiring
what it hopes will be a blockbuster for a deadly blood condition called hyperkalemia.
The next month, it announced it was purchasing a 55 percent stake in Acerta Pharma
BV for $4 billion, gaining access to a potential blockbuster medicine for blood cancer
(14 PLIR 19, 1/1/16).

Nonetheless, Nisen said, “They're going to have a tough time for the next few years.”

A return to the company's peak profitability years of 2010 and 2011 is “going to be
some years in the future.”

“I'm not sure they're quite there yet with trying to make up the drop-off in revenue
from Crestor and Nexium,” he added.

Actavis Generic Launched

Meanwhile, there is already one generic version of Crestor on the market. Watson Laboratories,
Inc. (now part of Actavis Inc.) began to market a generic version of Crestor May 2
under the terms of a license AstraZeneca granted to it under a 2013 patent litigation
settlement (11 PLIR 411, 3/29/13).

AstraZeneca said that the license it granted to Watson for the Crestor generic includes
a “selective waiver of all periods of exclusivity applicable to FDA’s May 27, 2016,
approval of the pediatric HoFH indication and labeling with respect to Watson’s marketing
of its generic rosuvastatin product.”

Until the pediatric exclusivity on Crestor expires in July, Actavis is required to
pay AstraZeneca a fee equal to 39 percent of net sales of the Actavis generic.

Actavis has global and U.S. headquarters in Parsippany, N.J., and international headquarters
in Zug, Switzerland.

AstraZeneca is based in the United Kingdom.

To contact the reporter on this story: Dana A. Elfin in Washington at
delfin@bna.com

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